Optimal therapeutic targeting by HDAC inhibition in biopsy-derived treatment-naïve diffuse midline glioma models

Abstract

Background Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis with less than 2% surviving 5-years post-diagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically-relevant DMG models to identify and validate other effective HDACi and their biomarkers of response. Methods HDACi were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically-relevant radiation-resistance. RNA sequencing was performed to define and compare drug efficacy, and to map predictive biomarkers of response. Results Quisinostat and romidepsin showed efficacy with a low nanomolar IC50 values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all three drugs at similar biologically effective doses, such as overexpression of TNNT1 and downregulation of COL20A1, identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (p <0.0001) inhibited in vivo tumor growth. Conclusions Our data highlights the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain-tumor-penetrant versions of potentially efficacious agents.

MRI-based radiomics for prognosis of pediatric diffuse intrinsic pontine glioma: an international study

“… 4 Furthermore, preclinical studies have often found that even epigenetically targeted agents such as HDAC inhibitors are still efficacious against histone wildtype DIPG, supporting some inherent similarities despite molecular distinctions. 51 , 52 While, it would be desirable to identify radiomic features unique to the H3 K27M-mutant subgroup, this was not feasible due to lack of biopsy in the majority of the cases. As biopsy becomes more common, prospective associations between artificial intelligence-based imaging and genomics may provide further insight.…”

Analysis of multi-omics differences in left-side and right-side colon cancer

“…Among the key genes, C1ORF105 was associated with a larger inter-adventitial common carotid artery diameter (ICCAD) (Harrison et al, 2013), and FAM132b can be increased by induction of erythrogenesis (Gurieva et al, 2017), suggesting that they may play an important role in the occurrence and development of cancer. The overexpression of TNNT1 may play a role in the development of diffuse midline gliomas (DMGs) (Vitanza et al, 2020). RspO4 can activate the Wnt/β-catenin signaling pathway and promote the progression of esophageal squamous cell carcinoma (Chai et al, 2020).…”

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

“…For this reason, acknowledging the susceptibility of the different glioma molecular subtypes to different treatments to induce ICD. For example, HDAC inhibitors were shown to target K27M HGG ( 260 ), and other tailored therapies are being explored for other subtypes ( 252 ), but the potential combinations of treatments inducing ICD and immunotherapies remain unexplored.…”